graves orbitopathy

Graves OrbitopathyRaed Behbehani , MD FRCSC

Graves Orbitopathy• 1-2% of women , 0.5% of men• Female : Male ratio , 5:1

GD Pathophysiology

Smith TJ et al. ENJM 2017

Systemic Signs and Symptoms• Eye signs usually start within a year of hyperthyroidism (75%)• Occasionally eye signs start years later.

Keratopathy

Superficial Punctate Keratitis Superior Limbic Keratoconjunctivitis

Lid retraction Pathogenesis : sympathetic stimulation , overaction of LPS alone with SR compensating for IR restriction , inflammation and fibrosis of levator palpebrae superioris muscle.

Clinical Features-Proptosis• Due to expansion of orbital fat and muscles.• Complete subluxation of the globe (sometimes)• Prolapse of the lacrimal glands • Corneal exposure/ epithelial defects

CT in TED• Enlargement of EOM ,

lacrimal glands, anterior soft tissue swelling , prominent superior ophthalmic vein.

• Bone remodeling (medial wall)

MRI in TED• High T2 in EOM - active stage

( high water content) , good prognostic sign for response to XRT and steroids

• Low T2 in EOM- inactive fibrotic stage

Strabismus• 30% of patients with TED.• Diplopia can be intermittent or constant• Inferior Recti , Medial Recti (most common)

Compressive Optic Neuropathy• 5%-7% of TED• Direct compression of the optic nerve at the orbital apex • Dyschromatopsia , RAPD .• Optic Disc edema in 40%• Visual fields• Often in the active phase of the disease• Proptosis may be minimal (tight lids)

Thyroid CON

Natural History of Thyroid Eye Disease

• Rundle’s curve• Progressive phase lasting for up to 18 months• Stable (inactive) phase

Risk Factors for Graves Orbitopathy• Smoking • Hypothyroidism following radio-iodine treatment • Positive family history of auto-immune disease• Increasing age• Life stressors

Smoking and TED• A meta-analysis showed smoking increases the risk of TED Vestergaard

at al. 2002

Odds ratio (95% CI)

GD vs Controls

Current smoker vs Never Smoker 3.3 (2.09-5.22)

GO vs Controls

Ever smoker vs never smoker 4.4 (2.88-6.73)

GO = Graves Ophthalmopathy GD= Graves disease

Smoking and TED – Dose Response• Relative risk of proptosis increased with smoking. (Pfeilschifter et al. Clin

Endocrnol. 1996)

• Smoking was predictive of severe TED (OR= 6.57) and optic neuropathy (OR=10) (Lee JH et al. Korean J Ophthalmol 2010)

Smoking cig/day Relative risk of Proptosis

1-10 1.8

11-20 3.8

>20 7

Smoking risk for TED specific GD.• OR for toxic nodular goitre is only 1.22 .• Smoking is associated with lower occurrence of anti-TPO and anti-

thyroglobulin Ab (Hashimoto’s thyroiditis).• Confounding factors (iodine intake , stressors, alcohol)

Smoking and TED• A 30 year old man with protruding

eyes for 5 months.• He was diagnosed with GD 6

months ago and started on Inderal and neomercazole.

• Euthyroid• Heavy smoker (2-3 packs/day)

Radio-iodine ablation (RAI) and TED• RAI is associated with 15% chance of TED . (Bartalena et al. NEJM 1998)

• Risk is reduced with a course of steroids. (Traisk et al. J Clin Enocrinol Metab. 2009)

• Smoking increase risk of worsening post-RAI 4-fold vs. non-smokers.• Response to steroids is 4-fold less likely in smokers vs. non-smokers.

RAI and TED

• Risk of development or worsening GO with RAI vs ATD (OR 2.25)• Steroid prophylaxis reduced risk by 60%.• Total Thyroid ablation (near total thyroidectomy or RAI) did show

significant beneficial effect on the improvement of GO (OR 6.0)• Early administration of levothyroxine after RAI therapy reduces the

occurrence of GO. (Tallstedt L et al. Eur J Endocrinol 1994)

RAI and TED• EUGOGO : Post-RAI steroid prophylaxis with risk factors for worsening

of TED (pre-treatmemt FT3, smoking, pre-exsiting TED, hypothyroidism).

• Steroid Dose: 0.3—0.5 mg/kg prednisone for 4-6 weeks

Clinical Activity• EUGOGO Assessment• CAS• VISA

Clinical Activity (CAS) • Binary scale • 1 point for each periocular soft tissue inflammatory sign. • Points for proptosis ( 2 mm or more) , decreased motility (8 degrees or

more) or decreased visual acuity over last 3 months.• Active GO = CAS ≥3 • CAS > 4 means 80% PPV for response to steroids

VISA classification • V (Vision) , I (inflammation), S (Strabismus) , A (Appearance)• Score of 5 or more —> Active disease or progression (Consider

Steroids)

VISA Classification

EUGOGO Assessment• Mild – minor impact of daily life , lid retraction <2 mm, Proptosis <3

mm , mild soft tissue swelling.• Moderate-to-Severe - Significant impact on daily life , lid retraction >2

mm , Proptosis > 3mm , moderate-severe soft tissue swelling , Diplopia• Sight-threatening – Optic Neuropathy , Severe corneal exposure

Selenium • 200 ug/day for 6 months• For Mild disease• Antioxidant effect• Immunomodulatory effect : reduce thyroid autoantibodies • Reduce severity of disease and improve QOL

Corticosteroids• IV pulses are more effective than oral (70%-80% vs 50%) with less

adverse events (39 vs. 81%.) (Zang S et al. J Clin Endocrinol Metab 2011; Stiebel-Kalish at al. J Clin Endocrinol Metab 2009)

• IV dose (max 8 grams) : 500 mg weekly for 6 weeks and then 250 mg weekly for 6 weeks.

• Improvement is related to cumulative dose.• Steroid response is evident usually 2-4 weeks late

Rituximab• Chimeric mono-clonal CD20 antibody .• CD20 is expressed on more than 95% of B cells and plasma cells• For steroid-refractory disease• Side effects : Allergic reaction (mild) PML (severe)

Rituximab• At 24 weeks 100% of RTX patients improved compared with 69% after

IV Steroids (P < .001) (Salvi et al. J Clin Endocrinol Metab 2015)

• RTX offered no additional benefit over placebo to our patients with active and moderate-to-severe GO (Stan MN et al. J Clin Endocrinol Metab 2015)

Orbital Radiation (OR)• Mechanism : lymphocyte sterilization, destruction of tissue monocytes • 20 Gy in 10 divided sessions over 2 weeks• May have a role in patients with TED who have restricted ocular

motility or active disease• Some studies have shown benefit (controversial)• More suited for patients > 35 years of age• Contra-indicated in pre-existing retinopathy (diabetes , hypertensive)

Orbital Decompression for TED• In severe corneal exposure or/or compressive optic neuropathy.• Cosmetic for rehabilitation in stable phase.• Post-operative complications (diplopia, vision loss)• Outcome is variable : degree of fibrosis , fat expansion , bone

available, duration of optic neuropathy .

Orbital Decompression Fat only (First Wall)

2-3 mm

Lateral Wall 3-6 mm

Medial Wall 4-7

Orbital Roof 5-9 mm

Orbital Decompression

Before surgery

After 3 wall decompression

Strabismus Surgery for TED• In the stable phase with stable alignments for 6 months• Press-on Fresnel/Botox as temporizing measure• Single binocular vision in primary and reading position• Conjunctival dissection is challenging.

Upper Lid Retraction

• Levator recession / Mullerectomy• Full-thickness blepharotomy• Botox injections into Muller’s muscle (transient)• Filler (Hyaloronic acid) in subcinjunctival space (0.1-0.2

ml)

Lower Lid retraction • Can improve with decompression and

removal of the floor basin.• Lower lid recession with decompression.• Spacer (ear cartillage or hard

palate/allogenic material)

Psychological Impact and Quality of Life in TED

• Studies suggest low QOL equivalent to diabetes and cancer (Kahaly GJ et al. Clin Endocrinol Oxf 2005)

• Disfigurement/altered facial appearance • Almost 50% of TED suffer depression and/or anxiety• 90% of TED have appearance concerns (young females)

Graves disease Mimickers• Inflammatory (IOIS , CCF , Orbital Vascular lesions, Sarcoidosis)• Neoplastic (Lymphoma , lacrimal gland tumors , meningioma)• Motility (Myasthenia , cranial nerve palsy , Orbital Myositis , orbital

apex and cavernous sinus lesions)• Lid retraction (contralteral ptosis)

Graves Ophthalmopathy Mimickers

Summary• Graves is inflammatory orbital disease characterized by proptosis , lid

retraction and changes in the periorbital tissues.• Smoking is a risk factor for severe TED and poor response to therapy.• RAI is associated with GO and risk is minimized with steroids and post-

hypothyroidism treatment.• IV steroids are more effective and safer than oral steroids.• Surgery for GO is indicated for corneal exposure and optic neuropathy

and cosmetic rehabilitation• Multidisciplianary , patient-focused approach is important.

Case• A 53 year old presents on 28/1/2017 with “sudden onset of proptosis”

started 5/12/2016. • He denies any pain , diplopia or decreased vision. • He was seen by an ophthalmologist and diagnosed as “orbital

pseudotumor” and received IV steroids followed by oral steroids for 2 months.

• No improvement of proptosis following steroids. • Thyroid functions were “normal” , except at one time , and it then

normalized again.• Family history of thyroid disease in sister.

Case

Hertel Exophthalmometry

20 OD 28 OS Base 115

CaseTest 26/1/2017 8/1/2017 29/11/2016 Reeference

TSH 0.623 0.441 0.005 0.27-4.2 mIU/L

Free T4 13.2 12.6 21.8 12-22 pmol/L

Anti-Thyroperoxidase Ab negative

Anti-TSH Receptor Ab negative

CRP

C-ANCA , P-ANCA

Ant—nRNP/SM

Anti-Sm

Anti-SSA

Anti-Ro-52

Anti-SS-B

Anti-Scl-70

Anti-PM-Sci

Anti-Jo-1

Anti-Centromere

Anti-PCNA

Ant-ds-DNA

Anti-nucleosomes

Anti-Histones

Anti-Ribosomal-P-Protein

Anti-AMA-M2-IgG

Urnianlysis – normalT3- 1.23T4- 7.40TSH – 1.09

24/2/2017

graves orbitopathy

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